scholarly journals Deletion of arginase 2 attenuates neuroinflammation in an experimental model of optic neuritis

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247901
Author(s):  
Amritha A. Candadai ◽  
Fang Liu ◽  
Abdelrahman Y. Fouda ◽  
Moaddey Alfarhan ◽  
Chithra D. Palani ◽  
...  
Keyword(s):  
Optic Neuritis ◽  
Experimental Model ◽  
Axonal Degeneration ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Optic Nerves ◽  
Clinical Presentations ◽  
Retinal Neurodegeneration ◽  
The Impact ◽  
Experimental Autoimmune

Vision impairment due to optic neuritis (ON) is one of the major clinical presentations in Multiple Sclerosis (MS) and is characterized by inflammation and degeneration of the optic nerve and retina. Currently available treatments are only partially effective and have a limited impact on the neuroinflammatory pathology of the disease. A recent study from our laboratory highlighted the beneficial effect of arginase 2 (A2) deletion in suppressing retinal neurodegeneration and inflammation in an experimental model of MS. Utilizing the same model, the present study investigated the impact of A2 deficiency on MS-induced optic neuritis. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2-/-) mice. EAE-induced cellular infiltration, as well as activation of microglia and macrophages, were reduced in A2-/- optic nerves. Axonal degeneration and demyelination seen in EAE optic nerves were observed to be reduced with A2 deletion. Further, the lack of A2 significantly ameliorated astrogliosis induced by EAE. In conclusion, our findings demonstrate a critical involvement of arginase 2 in mediating neuroinflammation in optic neuritis and suggest the potential of A2 blockade as a targeted therapy for MS-induced optic neuritis.

scholarly journals Tissue-specific expression of B7x protects from CD4 T cell–mediated autoimmunity

2011 ◽  
Vol 208 (8) ◽  
pp. 1683-1694 ◽  
Author(s):  
Joyce Wei ◽  
P’ng Loke ◽  
Xingxing Zang ◽  
James P. Allison
Keyword(s):  
T Cells ◽  
Pancreatic Islets ◽  
Peripheral Tolerance ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Specific Expression ◽  
Tissue Specific ◽  
Disease Induction ◽  
Deficient Mice ◽  
Experimental Autoimmune

B7x, an inhibitory member of the B7/CD28 superfamily, is highly expressed in a broad range of nonhematopoietic organs, suggesting a role in maintaining peripheral tolerance. As endogenous B7x protein is expressed in pancreatic islets, we investigated whether the molecule inhibits diabetogenic responses. Transfer of disease-inducing BDC2.5 T cells into B7x-deficient mice resulted in a more aggressive form of diabetes than in wild-type animals. This exacerbation of disease correlated with higher frequencies of islet-infiltrating Th1 and Th17 cells. Conversely, local B7x overexpression inhibited the development of autoimmunity, as crossing diabetes-susceptible BDC2.5/B6g7 mice to animals overexpressing B7x in pancreatic islets abrogated disease induction. This protection was caused by the inhibition of IFN-γ production by CD4 T cells and not to a skewing or expansion of Th2 or regulatory T cells. The suppressive function of B7x was also supported by observations from another autoimmune model, experimental autoimmune encephalomyelitis, in which B7x-deficient mice developed exacerbated disease in comparison with wild-type animals. Analysis of central nervous system–infiltrating immune cells revealed that the loss of endogenous B7x resulted in expanded Th1 and Th17 responses. Data from these two autoimmune models provide evidence that B7x expression in the periphery acts as an immune checkpoint to prevent tissue-specific autoimmunity.

scholarly journals Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE

2020 ◽  
Author(s):  
P Chaudhary ◽  
GH Marracci ◽  
E Calkins ◽  
E Pocius ◽  
AL Bensen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Axonal Degeneration ◽  
List Type ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Thyroid Receptor ◽  
Oligodendrocyte Precursor ◽  
Receptor Beta ◽  
Experimental Autoimmune ◽  
Degenerating Axons

AbstractWe have previously demonstrated that thyromimetics stimulate oligodendrocyte precursor cell differentiation and promote remyelination in murine demyelination models. We investigated whether a thyroid receptor-beta selective thyromimetic, sobetirome (Sob), and its CNS-targeted prodrug, Sob-AM2, could prevent myelin and axonal degeneration in experimental autoimmune encephalomyelitis (EAE). Compared to controls, EAE mice receiving triiodothyronine (T3, 0.4mg/kg), Sob (5mg/kg) or Sob-AM2 (5mg/kg) had reduced clinical disease and, within the spinal cord, less tissue damage, more normally myelinated axons, fewer degenerating axons and more oligodendrocytes. T3 and Sob also protected cultured oligodendrocytes against cell death. Thyromimetics thus might protect against oligodendrocyte death, demyelination and axonal degeneration as well as stimulate remyelination in multiple sclerosis.HighlightsThyroid hormone, the thyromimetic Sob and its CNS penetrating prodrug, Sob-AM2, reduce disease severity, reduce myelin and axonal degeneration and protect oligodendrocytes in EAE.The benefits of Sob and Sob-AM2 may be via direct protective effects on oligodendrocytes and reduction in activity of microglia/macrophages.

Effect of geranylgeranylacetone on optic neuritis in experimental autoimmune encephalomyelitis

2009 ◽  
Vol 462 (3) ◽  
pp. 281-285 ◽  
Author(s):  
Xiaoli Guo ◽  
Chikako Harada ◽  
Kazuhiko Namekata ◽  
Kenji Kikushima ◽  
Yoshinori Mitamura ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Optic Neuritis ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

scholarly journals Impact of High Intensity Exercise on Muscle Morphology in EAE Rats

2015 ◽  
pp. 907-923 ◽  
Author(s):  
I. WENS ◽  
U. DALGAS ◽  
K. VERBOVEN ◽  
L. KOSTEN ◽  
A. STEVENS ◽  
...  
Keyword(s):  
Muscle Fiber ◽  
High Intensity ◽  
High Intensity Exercise ◽  
Muscle Performance ◽  
Autoimmune Encephalomyelitis ◽  
Cross Sectional ◽  
Muscle Work ◽  
General Exercise ◽  
The Impact ◽  
Experimental Autoimmune

The impact of high-intensity exercise on disease progression and muscle contractile properties in experimental autoimmune encephalomyelitis (EAE) remains unclear. Control (CON) and EAE rats were divided into sedentary and exercise groups. Before onset (experiment 1, n=40) and after hindquarter paralysis (experiment 2, n=40), isokinetic foot extensor strength, cross sectional area (CSA) of tibialis anterior (TA), extensor digitorum longus (EDL) and soleus (SOL) and brain-derived neurotrophic factor (BDNF) levels were assessed. EAE reduced muscle fiber CSA of TA, EDL and SOL. In general, exercise was not able to affect CSA, whereas it delayed hindquarter paralysis peak. CON muscle work peaked and declined, while it remained stable in EAE. BDNF-responses were not affected by EAE or exercise. In conclusion, EAE affected CSA-properties of TA, EDL and SOL, which could, partly, explain the absence of peak work during isokinetic muscle performance in EAE-animals. However, exercise was not able to prevent muscle fiber atrophy.

scholarly journals Lowering blood cholesterol does not affect neuroinflammation in experimental autoimmune encephalomyelitis

2021 ◽  
Author(s):  
solenne vigne ◽  
Donovan Duc ◽  
Yannick Yersin ◽  
Jessica Rebeaud ◽  
Florian Ruiz ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Cholesterol Level ◽  
Blood Cholesterol ◽  
Lipid Lowering ◽  
Blood Levels ◽  
Disease Course ◽  
Blood Cholesterol Level ◽  
Autoimmune Encephalomyelitis ◽  
The Impact ◽  
Experimental Autoimmune

Abstract Background: Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS) commonly affecting young adults. There is increasing evidence that environmental factors are important in the development and course of MS. Metabolic syndrome (MetS) including dyslipidemia has been associated with a worse outcome in MS disease. Furthermore, the lipid lowering drugs statins have been proposed to improve MS disease course. However, cholesterol is also rate-limiting for myelin biogenesis and promotes remyelination in MS animal models. Thus, the impact of circulating blood cholesterol level during the disease remains debated and controversial. Methods: We assessed the role of circulating cholesterol on the murine model of MS, the experimental autoimmune encephalomyelitis (EAE) disease using two different approaches: 1) the mouse model of familial hypercholesterolemia induced by low density lipoprotein receptor (LDLr) deficiency, and 2) the use of the monoclonal anti-PCSK9 neutralizing antibody alirocumab which reduces LDLr degradation and consequently lowers blood levels of cholesterol. Results: Elevated blood cholesterol levels induced by LDLr deficiency did not worsen clinical symptoms of mice during EAE. In addition, we observed that the anti-PCSK9 antibody alirocumab did not influence EAE disease course, nor modulate the immune response in EAE. Conclusions: These findings suggest that blood cholesterol level has no direct role in neuro-inflammatory diseases and that the previously shown protective effects of statins in MS are not related to circulating cholesterol.

scholarly journals Astrocytic YAP Protects the Optic Nerve and Retina in an Experimental Autoimmune Encephalomyelitis Model Through TGF-β Signaling

2021 ◽  
Author(s):  
qian Wu ◽  
Xuemeng Miao ◽  
Jingjing Zhang ◽  
Ludan Xiang ◽  
Xiuchun Li ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Optic Neuritis ◽  
Transforming Growth Factor ◽  
Conditional Knockout ◽  
Gene Set Enrichment Analysis ◽  
Tunel Staining ◽  
Autoimmune Encephalomyelitis ◽  
Gene Set ◽  
Experimental Autoimmune

Abstract BackgroundOptic neuritis, inflammation of the optic nerve (ON), is one of the main symptoms in multiple sclerosis (MS) and leads to visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS. However, it remains unclear that the detailed roles and mechanisms of astrocytes in the neuroinflammation and demyelination in optic neuritis of MS. MethodsTo assess the role of YAP in ON and retina in response to experimental autoimmune encephalomyelitis (EAE), mice that conditionally knockout (CKO) YAP in astrocytes, namely YAP GFAP -CKO mice, were successfully generated. Immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, luxol fast blue (LFB) staining, electron microscopy (EM), qRT-PCR and gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the roles of YAP pathway in EAE based on these conditional knockout mice. Inhibitors including SRI-011381 [an agonist of transforming growth factor-β (TGF-β) pathway] and XMU-MP-1 (an inhibitor of Hippo kinase MST1/2 to activate YAP) were used to further explore the molecular mechanism of YAP in ON and retina of EAE mice. Additionally, microglia and retinal ganglion cells (RGCs) counts, and demyelination and astrocytes were assessed by immunohistological staining. ResultsWe found that yes-associated protein (YAP) was significantly upregulated and activated in the astrocytes of ON in EAE. Conditional knockout YAP in astrocytes caused more severe inflammatory infiltration and demyelination in ON, and damage of the RGCs in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of ON in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes . Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β 1 in YAP knockout ON astrocytes of EAE mice. Interestingly, SRI-011381 partially rescued the deficits in ON and retina of YAP knockout EAE mice. Finally, activation of YAP pathway relieved the neuroinflammation and demyelination in optic neuritis of EAE mice. ConclusionsThese results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for optic neuritis in MS.

scholarly journals CD169 is a marker for highly pathogenic phagocytes in multiple sclerosis

2017 ◽  
Vol 24 (3) ◽  
pp. 290-300 ◽  
Author(s):  
Jeroen FJ Bogie ◽  
Ellen Boelen ◽  
Els Louagie ◽  
Peter Delputte ◽  
Dirk Elewaut ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Encephalomyelitis ◽  
Highly Pathogenic ◽  
Disease Symptoms ◽  
Effector Cells ◽  
Diphtheria Toxin Receptor ◽  
Therapeutic Value ◽  
Toxin Receptor ◽  
The Impact ◽  
Experimental Autoimmune

Background: Phagocytes, such as macrophages and microglia, are key effector cells in the pathophysiology of multiple sclerosis (MS). It is widely accepted that they instigate and promote neuroinflammatory and neurodegenerative events in MS. An increasing amount of studies indicate that Siglec-1, also known CD169, is a marker for activated phagocytes in inflammatory disorders. Objective: In this study, we set out to define how CD169+ phagocytes contribute to neuroinflammation in MS. Methods: CD169-diphtheria toxin receptor (DTR) mice, which express human DTR under control of the CD169 promoter, were used to define the impact of CD169+ cells on neuroinflammation. Flow cytometry and immunohistochemistry were utilized to determine the expression and distribution of CD169. Results: We show that CD169 is highly expressed by lesional and circulating phagocytes in MS and experimental autoimmune encephalomyelitis (EAE). Our data further indicate that CD169 represents a selective marker for early activated microglia in MS and EAE lesions. Depletion of CD169+ cells markedly reduced neuroinflammation and ameliorated disease symptoms in EAE-affected mice. Conclusion: Our findings indicate that CD169+ cells promote neuroinflammation. Furthermore, they suggest that CD169+ phagocytes play a key role in the pathophysiology of MS. Hence, targeting CD169+ phagocytes may hold therapeutic value for MS.

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